ABSTRACT
A new glucuronylated prodrug of doxorubicin, potentially useful for ADEPT or PMT cancer chemotherapy, has been prepared from 4-methyl phenyl malonaldehyde. The enol ether spacer, linked via a carbamate to the 3'-amino group of doxorubicin is rapidly cleaved after beta-glucuronidase (E coli) catalyzed hydrolysis at pH 7.2 and 37 degrees C.
Subject(s)
Antibiotics, Antineoplastic/chemical synthesis , Doxorubicin/analogs & derivatives , Glucuronates/chemistry , Prodrugs/chemical synthesis , Antibiotics, Antineoplastic/chemistry , Doxorubicin/chemistry , Glucuronidase/metabolism , Models, Chemical , Molecular Structure , Prodrugs/chemistryABSTRACT
A new glucuronylated prodrug of nornitrogen mustard, incorporating the same spacer group as the doxorubicin prodrug HMR 1826, has been prepared. Upon exposure to E. coli beta-glucuronidase, fast hydrolysis occurs but a lower cytotoxicity against LoVo cancer cells is observed compared to the nornitrogen mustard alone. This is explained by cyclization of the intermediate carbamic acid to the inactive chloroethyl oxazolidinone.